Cancer is recognized as one of the diseases mediated by the signal transduction system or signal transduction mechanism in cell. The proliferation of cell is directed by many extracellular orders received by the cell. The aim of the signal transduction system is to receive these or other signals from the surface of the cell, and to introduce them into the cell. Then these signals are transmitted into nucleolus and skeleton of the cell, which affect the transcription of gene and the synthesis of protein.
The most common pathogenesis of cancer is a series of defects. Said defects can be the defects of some proteins (when mutation occurs), or the lack of regulation of the amount of proteins in cell, which results in excessive or deficient production of some proteins. Generally, the constitutive state can be induced by the serious injury in cell, and hence the signal for proliferation is received by the nucleus while these signals do not exist in fact. The occurrence of such case may result from many mechanisms. Sometimes, some corresponding growth factors of their autoreceptors are produced by cell in an inappropriate way, which is the so called autocrine loop mechanism.
There are many receptors existing on the cell surface. The interaction between growth factors and these receptors is required for the normal regulation of cell growth. However, in some case, the mutation or overexpression of any of these receptors will result in abnormal receptors and hence the uncontrolled proliferation of the cell, which may result in tumor cells and cancer in the end.
Epidermal growth factors receptors (EGFR) are identified as a significant driving factor in the growth and proliferation process of cell. In common tumors, such as non-small cell lung cancer, epidermal growth factors receptors are expressed excessively, which is far beyond the normal range. The epidermal growth factors receptor family consists of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4. The epidermal growth factors receptors are related to the progression of most cancers, especially colonic cancer and mammary cancer. The overexpression of said receptors has been confirmed as the primary risk factor for a poor-prognosis mammary cancer. Besides, it has been confirmed that all of the above four members of the receptor family can polymerize with other member of the family to form a heterodimer, forming the signal transduction complex. The overexpression of more than one member of said family in malignant cells will result in the cooperation of the signal transduction.
EGFR belongs to the protein tyrosine kinase (PTK) family. The protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosine residues located on the protein substrate. Protein tyrosine kinases play important roles in normal cell growth. The overexpression of EGFR may cause the activation of receptors without ligands and the phosphorylation of certain protein, and then the fissional signal is given. As a result, EGFR may magnify the weak signal excessively by the auto-tyrosine-kinases action, which results in excessive cell proliferation.
Due to the important effect of the abnormal receptor tyrosine kinases on the pathogenesis of cancer, many of the recent researches relate to specific PTK inhibitors as potential anti-cancer drugs. European patent application EP520722A1 discloses some 4-phenylamino-phthalazinone derivatives with PTK inhibitory activity. European patent application EP566226A1 discloses some 4-phenylamino-phthalazinone derivatives with a plurality of substituents at positions 5 to 8 thereof having PTK inhibitory activity. European patent application EP635498A1 discloses some 4-phenylamino-phthalazinone derivatives having PTK inhibitory activity, which must contain one halogen substituent at position 7 and a plurality of substituents at position 6.
WO 96/30347 (Chinese patent application CN 96102992) relates to a series of 4-(substituted-phenylamino)-quinazoline derivatives, their prodrug, their pharmaceutically acceptable salts and their uses in treating diseases induced by over proliferation.
WO 97/38983 (Chinese patent application CN 97194458) provides the compounds as irreversible inhibitor of tyrosine kinases.
WO 99/35146 (Chinese patent application CN 99803887) discloses bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors.
WO 00/06555 (Chinese patent application CN 99808949) also relates to substituted quinazoline derivatives having PTK inhibitory activity.
WO 2006/071017 also mentions some quinazoline derivatives that inhibit growth of cancer cells.
PCT/CN2006/002786, filed by the applicant of the present invention on Oct. 20, 2006, describes a novel type of 4-phenylamino quinazoline derivatives and their uses as PTK inhibitors, wherein, it is proven by experiments that the compound N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide obtained in Example 8 possesses relatively good inhibitory activity of human epidermoid squamous cancer cells A431 and human mammary cancer cells BT-474. The compound also possesses conspicuous anti-tumor effect on human epidermoid squamous cancer cells A431 transplanted to a nude rat. It is also proven in vitro that the compound has excellent inhibitory activity against Erb-B2. The contents of the document are hereby incorporated in their entireties by reference herein.